CN1125725A - First-kind "Haikelin" alkali derivant and its usage - Google Patents
First-kind "Haikelin" alkali derivant and its usage Download PDFInfo
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- CN1125725A CN1125725A CN94114057A CN94114057A CN1125725A CN 1125725 A CN1125725 A CN 1125725A CN 94114057 A CN94114057 A CN 94114057A CN 94114057 A CN94114057 A CN 94114057A CN 1125725 A CN1125725 A CN 1125725A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The "Haikelin" alkali derivative that can be used as efficient inhibitor of choline esterase with low toxicity is prepared by condensation reaction of "Haikelin" alkali with substituted acid chloride or aldehyde in anhydrous solvent.
Description
It is semi-synthetic to the present invention relates to natural product, is specifically related to alkaloid and its analogue.
The external anticholinesterase raising interior cholinergic system function measure treatment of the brain degenerative brain disorder of using is carried out big quantity research over nearly 10 years, though obtained gratifying result of study, but also there are many shortcomings, when therapeutic action occurring, more serious toxic reaction is arranged, and acting duration is shorter.
China separates from the herbal medicine Herba Lycopodii serrati and obtains new alkaloid selagine (11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene cyclooctene is [b] pyridine-2 (1H)-ketone (Compound I) also for 5R, 9R in recent years
It has potent reversible anticholinesterase activity through the pharmacological research proof, to the selective restraining effect of acetylcholinesterase in the brain [United States Patent (USP) 5177082], selagine is carried out structure of modification and synthetic selagine analogue abroad, wish therefrom to find to have the method [United States Patent (USP) 4929731] of the compound [J.Org Chem 56 1991 (4636-4645)] of anticholinesterase activity and the complete synthesis selagine of searching but do not find good method as yet, also do not find the analogue of better effect.
It is semi-synthetic that the present invention utilizes the resources advantage of China's herbal medicine to design to carry out from selagine, wishes to seek out from many huperzine A derivatives compound better than existing huperzine alkali first effect and that toxicity is lower.
The present invention implements through the following steps:
From the Herba Lycopodii serrati plant through alcohols such as ethanol as extracting solvent, concentrated residue obtained water layer neutralizes with alkali through mineral acid (example hydrochloric acid) processing, and alkalization is (as ammoniacal liquor, NaOH) with organic solvent (as chloroform) extract total alkaloids, treated, chromatographic separation obtains compound (I).
2. compound (I) is through with corresponding replacement aldehyde or carry out condensation with corresponding replacement acyl chlorides in anhydrous solvent and get general formula (II)
Y is
Or-CHR is low alkyl, substituted-phenyl, substituted heterocyclic radical, replacement cinnamyl etc.
The pharmacological action of huperzine A derivative:
The present invention uses the restraining effect of the colorimetric method for determining medicine of Ellman report to enzyme activity.Enzyme activity reaction solution total volume is 4ml, include acetylthiocholine iodide 0.3mmol/L (acetylcholinesterase substrate), or sulfur iodide is for the damping fluid 1ml of BuCh 0.4mmol/L (butyrylcholine esterase substrate) PH7.4 phosphoric acid salt 25mmol/L, add water at last and supply 4ml (comprising enzyme-added liquid measure in back and test soup), 37 ℃ of insulations are after 5 minutes, add enzyme liquid (rat erythrocyte membrane or rat blood serum) 0.1-0.2ml or add test soup 0.1-0.3ml simultaneously, be incubated 8 minutes again and add 1ml 3% sodium lauryl sulphate termination reaction, add 1ml 0.2% 5 at last, 5 '-connection sulphur-2,2 '-nitro-benzoic acid solution colour developing is measured optical density(OD) with " 721 " spectrophotometer in 440nm.With enzyme activity (the being 100%) contrast of unconstrained medicine, medicine molconcentration is mapped the drug dose IC when trying to achieve inhibitory enzyme vigor 50% with the percentage ratio of residual enzyme vigor
50Test-results shows: derivative No1, and No7, No8, No9 all has the obvious suppression effect to acetylcholinesterase, is weaker than selagine slightly, but obviously is better than Physostigmine and lycoremine.They are weaker than selagine to the restraining effect of butyrylcholine esterase (false enzyme), derivative No1 and No7 suppress to show greater than selagine (seeing Table I) enzyme dynamics to the selectivity of acetylcholinesterase, derivative No7, No8 and No9 are reversible with combining of acetylcholinesterase.
With the passive escape of mouse operation (diving tower method) and two kinds of memory models test shows of rat eight arm labyrinth spatial discriminations operations, derivative No8, No9 all have the very strong dysmnesia effect (seeing Table 2,3) that improves, and their action intensity is similar to compound (I).
The acute toxicity test of mouse shows, the LD of derivative No.8 and No.9
50Less than compound (I), only be the latter's 1/3 (seeing Table 4)
Table 1, the external anticholinesterase effect (colorimetric method for determining) of huperzine A derivative
Suppress 50% enzyme activity concentration (IC
50μ M) IC
50Ratio compd B uChE
Acetylcholinesterase butyrylcholine esterase AChENo (ACHE) (BUCHE) 1 0.348 380.19 1092.5 2 9.05>346.7 3 3.63>331.1 4>12.88 58.9 5>10.96>275.4 6>12.3>309.1 7 0.172 199.5 1159.9 8 0.151 107.2 709.9 9 0.145 104.7 722.1 10>15.85 109.6 11>14.45 363 compounds (I), 0.06309 63.09 1000 eserine, 0.251 1.259 5.02 galanthamines, 1.995 12.59 6.3AChE takes from Rat Erythrocyte. BuChE takes from rat blood serum.
Table 2, huperzine A derivative improve the memory impairment of passive escape operation due to the scopolamine
Group dosage number of mice leave from office △ in latent period
(mg/kg ip+po) (only) (second ± SEM) physiological saline+physiological saline-+-20 71.9 ± 12.9 scopolamines+physiological saline 2+-20 29.5 ± 2.7
$$Scopolamine+derivative No8 2+0.2 20 67.7 ± 11.7**
2+0.3 20 64.0±9.8*
2+0.4 20 48.7 ± 6.9 physiological saline+physiological saline-+-18,81.7 ± 19.0 scopolamines+physiological saline 2+-23 32.3 ± 8.2
$$Scopolamine+derivative No9 2+0.1 11 48.9 ± 12.6
2+0.2 16 71.6±14.5
2+0.3 21 99.8±16.4**
2+0.4 18 92.2 ± 15.5* △: mouse is administration immediately after training earlier, test after 24 hours.
$$Compare * P<0.05, * * P<0.01 with physiological saline group comparison P<0.01** and eastern gelsemium henbane group
Table 3, huperzine derivative improve spatial discrimination operative memory infringement due to the scopolamine
Wrong-way number of times △ group dosage number of mice before up to standard
(mg/kg) (only) reference memory working memory
Ip+po (X+SEM) physiological saline+physiological saline-+-24 0.42 ± 0.1 0.08 ± 0.01 scopolamine+physiological saline 0.2+-6 1.67 ± 0.21
$$2.33 ± 0.42
$$Scopolamine+derivative No9 0.2+0.1 6 1.33 ± 0.21 1.33 ± 0.49
*
0.2 ± 0.3 6 0.33 ± 0.21
*0.17 ± 0.17
*Physiological saline+physiological saline-+-24 0.33 ± 0.13 0.08 ± 0.06 scopolamine+physiological saline 0.125+-6 2.0 ± 0.45
$$2.0 ± 0.52
$$Scopolamine+derivative No8 0.125+0.2 6 0.67 ± 0.33
*0.33 ± 0.13
*Physiological saline+physiological saline-+-14 0.21 ± 0.11 0.07 ± 0.07 scopolamine+physiological saline 0.15+-7 2.14 ± 0.14
$$2.57 ± 0.29
$$Scopolamine+selagine 0.15+0.25 10 0.57 ± 0.30
*0.86 ± 0.14
*△: eight arm labyrinths test.Rat up to standard through training (every day errors number below 1 time, for three days on end) after, be used for test.It is the reference memory mistake that rat enters the arm of not putting foodstuff for the first time.It is the working memory mistake that rat repeats to enter the arm of putting foodstuff.
$$Compare P<0.01 with physiological saline group comparison P<0.01** and eastern gelsemium henbane group.
Table 4, huperzine A derivative is to the acute toxicity (Bliss method) of mouse
Mg/kg p.o. (95% fiducial limit) * compound L D
5LD
5010 one group of compound (I) 3.1 (3.5-3.8) 4.6 (4.2-5.1) derivative No8 9.6 (7.3-12.5) 14.4 (12.8-16.4) derivative No9 11.1 (9.6-12.9) 14.1 (15.5-20.5) * mouse, ♀ ♂ half and half.Each medicine is tested with 4-5 dosage groups.
Observe the mortality ratio in 7 days.
Above-mentioned pharmacological experiments shows derivative No7, and No8, No9 are potent acetylcholinesterase selective depressants, and its acute toxicity is lower than compound (I), and therefore, they have the clinical application DEVELOPMENT PROSPECT inference.Be used for the treatment of the memory dysfunction that alleviation myasthenia gravis and central cholinergic system nonfunction cause.
Embodiment 1, the preparation of derivative No.2
Take by weighing compound (I) (0.50mmole) in the 50ml three-necked bottle, add the 20ml anhydrous pyridine, make (I) compound dissolution, ice under the molten cooling, splash into phenyllacetyl chloride (0.55mmole), after dropping was finished, room temperature was placed (25 ℃) the thin plate chromatography that spends the night and is shown that raw material disappears substantially, stopped reaction, water pump pressure reducing and steaming pyridine, separate with methylene dichloride with silica gel column chromatography: acetone: methyl alcohol=50: 45: 5 Xian take off thick product, acetone, sherwood oil mixed solvent recrystallization get product, yield 75%.UV λ
mox1=229nm(ε=17360)
λ
mox2=316nm(ε=9320)[α]
D 25℃=29.43°
1HNMR: 2H?6.31(1H,d,δ2,3=9.9HZ)[CDDCl
3]?3H?7.20(1H,d,δ2,3=9.9HZ)(400MHZ)?6H?2.89(1H?dd)
7H?3.52(1H?m)
8H?5.38(1H?d)
10-H?1.62(3H?d,J
10,11=6.7HZ)
11-H?5.08(1H?σ,J
10,11=6.7HZ)
14-H?2.15,2.45(2H),16-H,1.50(3H,S)
2’,6’-H?7.36(2H,d)
3’,5’-H?7.29(2H,m)
6’-H?7.24(1H,m)
7’-H?3.59(S)MS(m/z)360(M
+)345?269?252?227?224?210(100%)91mp: 171—173℃IR:(υ,cm
-1)3280,1660(S),1620(S),1550,1450,1350,1300,
1175,1130,840,620
Can make derivative No.1, No.5, No.6, No.10, No.11 with method.
Embodiment 2, the preparation of derivative No4
Take by weighing compound (I) (0.5mmole) in the 50ml three-necked bottle, add the 20ml anhydrous pyridine, make its dissolving, under the molten cooling of ice, add DBU (0.66mmole) earlier, 2-formyl chloride the pyridine hydrochloride that adds 0.55mmole again, room temperature is placed and is spent the night, show that with the thin plate measurement in chromatography reaction is complete substantially, with water pump pressure reducing and steaming pyridine, separate with silica gel column chromatography, developping agent is a methylene dichloride: acetone: methyl alcohol=Xian took off in 50: 45: 5, get thick product, get product yield 74% with acetone, sherwood oil mixed solvent recrystallization.UV λ
mox=226nm(ε=1.35×10
4)
λ
mox=264nm(ε=5.4×10
3)
λ
mox=315nm(ε=5730)[α]
D=77.85°
1HNMR:2H?6.36(1H,δ2.3=9.2HZ)[CDCl
3]3-H?7.44(1H,δ2,3=9.2HZ)(400MHZ)6-H?3.05(1H?dd)
7-H?3.74(1H?m)
8-H?5.42(1H?d)
10-H?1.65(3H?d,δ
10-11=6.6HZ)
11-H?5.35(1H?d,δ
10-11=6.6HZ)
14-H?2.42(2H)
16-H?1.55(S)
3’-H?8.58(1H,d)
4’-H?7.85(1H,q)
5’7.48(1H,m)
6’8.15(1H,d)MS(m/z)348(M
++1)347(M
+)241(100%)169,149,106,95,79,
71,55mp: 170—171℃IR:(υ,cm
-1)3450cm
-1,2900,1660(S),1615(S),1530(S),1460,
1300,1180,1140,1000,830,750
Embodiment 3, the preparation of derivative No8
Taking by weighing compound (I) (0.5mmole) is put in the 50ml three-necked flask, add dehydrated alcohol, add 4-methoxyl group, 5-hydroxy benzaldehyde (0.51mmole) reflux slightly, constantly steam part ethanol through water trap, and the solvent in the postreaction at any time, stoichiometric number hour is also used its reaction condition of thin plate measurement in chromatography at any time, treat fully after, ethanol is removed in decompression, get solid, product acetone, sherwood oil mixed solvent recrystallization get product, productive rate 92%.
Claims (3)
2.. compound according to claim 1 is characterized in that its preparation method is:
(1) as Y is
The time, selagine and corresponding replacement acyl chlorides carry out condensation in anhydrous solvent,
(2) when Y be-during HC, then the aldehyde of selagine and corresponding replacement carries out condensation in anhydrous solvent.
3. huperzine A derivative according to claim 1 is characterized in that it is the true cholinesterase selective depressant, can be used for treatment and alleviates myasthenia gravis, memory dysfunction that the central cholinergic system nonfunction causes and glaucoma.
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN94114057A CN1125725A (en) | 1994-12-28 | 1994-12-28 | First-kind "Haikelin" alkali derivant and its usage |
JP52010296A JP3545416B2 (en) | 1994-12-28 | 1995-12-26 | Huperzine A derivatives, their production and their use |
DK95941572T DK0806416T3 (en) | 1994-12-28 | 1995-12-26 | Huperzine derivatives, their preparation and use |
US08/860,524 US5929084A (en) | 1994-12-28 | 1995-12-26 | Huperzine A derivatives, their preparation and their use |
DE69530706T DE69530706T2 (en) | 1994-12-28 | 1995-12-26 | HUPERZINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE |
US09/799,127 USRE38460E1 (en) | 1994-12-28 | 1995-12-26 | Huperzine A derivatives, their preparation and their use |
AT95941572T ATE239708T1 (en) | 1994-12-28 | 1995-12-26 | HUPERZINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE |
AU42966/96A AU4296696A (en) | 1994-12-28 | 1995-12-26 | Huperzine a derivatives, their preparation and their use |
ES95941572T ES2199259T3 (en) | 1994-12-28 | 1995-12-26 | DERIVATIVES OF HUPERZINA, ITS PREPARATION AND ITS USE. |
PCT/CN1995/000100 WO1996020176A1 (en) | 1994-12-28 | 1995-12-26 | Huperzine a derivatives, their preparation and their use |
PT95941572T PT806416E (en) | 1994-12-28 | 1995-12-26 | HUPERZINE DERIVATIVES TO ITS PREPARATION AND UTILIZATION |
EP95941572A EP0806416B1 (en) | 1994-12-28 | 1995-12-26 | Huperzine a derivatives, their preparation and their use |
JP2003148129A JP4105592B2 (en) | 1994-12-28 | 2003-05-26 | Huperzine A derivatives, their preparation and their use |
JP2007174592A JP2007246545A (en) | 1994-12-28 | 2007-07-02 | Huperzine a derivative, method for producing the same and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN94114057A CN1125725A (en) | 1994-12-28 | 1994-12-28 | First-kind "Haikelin" alkali derivant and its usage |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1125725A true CN1125725A (en) | 1996-07-03 |
Family
ID=5037011
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94114057A Pending CN1125725A (en) | 1994-12-28 | 1994-12-28 | First-kind "Haikelin" alkali derivant and its usage |
Country Status (11)
Country | Link |
---|---|
US (1) | US5929084A (en) |
EP (1) | EP0806416B1 (en) |
JP (3) | JP3545416B2 (en) |
CN (1) | CN1125725A (en) |
AT (1) | ATE239708T1 (en) |
AU (1) | AU4296696A (en) |
DE (1) | DE69530706T2 (en) |
DK (1) | DK0806416T3 (en) |
ES (1) | ES2199259T3 (en) |
PT (1) | PT806416E (en) |
WO (1) | WO1996020176A1 (en) |
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US20070179123A1 (en) * | 2005-11-08 | 2007-08-02 | Chiang Peter K | Methods and compositions for treating diseases associated with pathogenic proteins |
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US8097726B2 (en) * | 2006-05-17 | 2012-01-17 | Industrial Technology Research Institute | Huperzine a compound for treatment of alzheimer's disease |
EP2044937A4 (en) * | 2006-07-05 | 2010-10-27 | Tianjin Hemay Bio Tech Co Ltd | ANALGESIC 5, 9 - METHANOCYCLOOCTA (b) PYRIDIN - 2 (1H) - ONE DERIVATIVES, THEIR PREPARATION METHOD AND USE |
TWI404531B (en) * | 2007-05-17 | 2013-08-11 | Ind Tech Res Inst | Huperzine a compound and pharmaceutical composition comprising the same |
WO2010028134A2 (en) * | 2008-09-04 | 2010-03-11 | President And Fellows Of Harvard College | Treatment of neurological disorders using huperzine |
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US5177082A (en) * | 1985-11-05 | 1993-01-05 | Yu Chao Mei | Huperzines and analogs |
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US4929731A (en) * | 1989-02-21 | 1990-05-29 | University Of Pittsburgh | Method for the synthesis of huperzine A and analogs thereof and compounds useful therein |
US5104880A (en) * | 1991-05-01 | 1992-04-14 | Mayo Foundation For Medical Education And Research | Huperzine a analogs as acetylcholinesterase inhibitors |
US5684018A (en) * | 1994-12-13 | 1997-11-04 | Merck & Co., Inc. | Acyloxyisopropyl carbamates as prodrugs for amine drugs |
-
1994
- 1994-12-28 CN CN94114057A patent/CN1125725A/en active Pending
-
1995
- 1995-12-26 PT PT95941572T patent/PT806416E/en unknown
- 1995-12-26 AT AT95941572T patent/ATE239708T1/en not_active IP Right Cessation
- 1995-12-26 JP JP52010296A patent/JP3545416B2/en not_active Expired - Fee Related
- 1995-12-26 ES ES95941572T patent/ES2199259T3/en not_active Expired - Lifetime
- 1995-12-26 AU AU42966/96A patent/AU4296696A/en not_active Abandoned
- 1995-12-26 WO PCT/CN1995/000100 patent/WO1996020176A1/en active IP Right Grant
- 1995-12-26 US US08/860,524 patent/US5929084A/en not_active Ceased
- 1995-12-26 EP EP95941572A patent/EP0806416B1/en not_active Expired - Lifetime
- 1995-12-26 DE DE69530706T patent/DE69530706T2/en not_active Expired - Fee Related
- 1995-12-26 DK DK95941572T patent/DK0806416T3/en active
-
2003
- 2003-05-26 JP JP2003148129A patent/JP4105592B2/en not_active Expired - Fee Related
-
2007
- 2007-07-02 JP JP2007174592A patent/JP2007246545A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100398093C (en) * | 2003-03-14 | 2008-07-02 | 德比欧药物研究有限公司 | Subcutaneous delivery system, process for the preparation of the same and use of the same for the treatment of cholinergic deficient disorders |
CN1308312C (en) * | 2003-11-13 | 2007-04-04 | 中国科学院上海药物研究所 | Huperzine B bimolecular and double function group devicative, preparing method and its use |
CN100528844C (en) * | 2007-04-20 | 2009-08-19 | 中国科学院昆明植物研究所 | Huperzine A derivative, preparation method and application thereof |
CN101797223B (en) * | 2009-02-06 | 2012-05-23 | 上海交通大学医学院 | Huperzine A preparations for eyes and application thereof |
Also Published As
Publication number | Publication date |
---|---|
ES2199259T3 (en) | 2004-02-16 |
DE69530706D1 (en) | 2003-06-12 |
AU4296696A (en) | 1996-07-19 |
PT806416E (en) | 2003-09-30 |
EP0806416A1 (en) | 1997-11-12 |
JP2007246545A (en) | 2007-09-27 |
DK0806416T3 (en) | 2003-09-01 |
DE69530706T2 (en) | 2004-03-25 |
JP4105592B2 (en) | 2008-06-25 |
US5929084A (en) | 1999-07-27 |
WO1996020176A1 (en) | 1996-07-04 |
EP0806416B1 (en) | 2003-05-07 |
ATE239708T1 (en) | 2003-05-15 |
JPH10511651A (en) | 1998-11-10 |
JP3545416B2 (en) | 2004-07-21 |
JP2003306481A (en) | 2003-10-28 |
EP0806416A4 (en) | 1998-04-15 |
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